Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression
Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression
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DOI：
10.1038/s41388-022-02525-1
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发表时间：
2022-11-05
期刊：
影响因子：
8
通讯作者：
Kuba, Keiji
中科院分区：
文献类型：
--
作者：
An, Jianbo;Nagaki, Yushi;Kuba, Keiji
转移预示癌症患者预后不良。人们已经认识到，特定的肿瘤微环境定义了癌细胞转移，而潜在的机制仍然难以捉摸。在这里，我们表明，半乳糖凝集素-7是一个重要的中介转移与免疫抑制。在NR-S1 M细胞的同基因小鼠鳞状细胞癌（SCC）模型中，我们从荷瘤小鼠的淋巴结中分离转移的NR-S1 M细胞，并在体外培养中建立转移的NR-S1 M细胞。RNA-seq分析显示，与亲本细胞相比，干扰素基因签名在转移性NR-S1 M细胞中显著下调，并且体内NR-S1 M肿瘤不均匀地发展出以抗肿瘤免疫细胞缺乏为特征的局灶性免疫抑制区域。NR-S1 M肿瘤的空间转录组分析（Visium）显示，与免疫活性区域相比，免疫抑制区域中的各种促转移基因显著上调。值得注意的是，半乳糖凝集素-7被鉴定为新的转移驱动因子。Galectin-7在肿瘤发生过程中，特别是在免疫抑制的微环境中被诱导表达，并在肿瘤进展的后期释放到细胞外。NR-S1 M细胞中半乳糖凝集素-7的缺失显著抑制淋巴结和肺转移，而不影响原发性肿瘤生长。因此，Galectin-7是SCC肿瘤转移的重要介质，在免疫抑制的肿瘤区域被培养，并且可能是癌症免疫治疗的潜在靶点。
Metastasis predicts poor prognosis in cancer patients. It has been recognized that specific tumor microenvironment defines cancer cell metastasis, whereas the underlying mechanisms remain elusive. Here we show that Galectin-7 is a crucial mediator of metastasis associated with immunosuppression. In a syngeneic mouse squamous cell carcinoma (SCC) model of NR-S1M cells, we isolated metastasized NR-S1M cells from lymph nodes in tumor-bearing mice and established metastatic NR-S1M cells in in vitro culture. RNA-seq analysis revealed that interferon gene signature was markedly downregulated in metastatic NR-S1M cells compared with parental cells, and in vivo NR-S1M tumors heterogeneously developed focal immunosuppressive areas featured by deficiency of anti-tumor immune cells. Spatial transcriptome analysis (Visium) for the NR-S1M tumors revealed that various pro-metastatic genes were significantly upregulated in immunosuppressive areas when compared to immunocompetent areas. Notably, Galectin-7 was identified as a novel metastasis-driving factor. Galectin-7 expression was induced during tumorigenesis particularly in the microenvironment of immunosuppression, and extracellularly released at later stage of tumor progression. Deletion of Galectin-7 in NR-S1M cells significantly suppressed lymph node and lung metastasis without affecting primary tumor growth. Therefore, Galectin-7 is a crucial mediator of tumor metastasis of SCC, which is educated in the immune-suppressed tumor areas, and may be a potential target of cancer immunotherapy.